Diagnosis of Zollinger–Ellison Syndrome in the Era of Ppis, Faulty Gastrin Assays, Sensitive Imaging and Limited Access to Acid Secretory Testing

Abstract

In recent years, the diagnosis of Zollinger–Ellison syndrome has become increasingly controversial with several new approaches and criteria proposed, differing from the classical biochemical criterion of inappropriate hypergastrinemia (i.e., hypergastrinemia in the presence of hyperchlorhydria). These changes have come about because of the difficulty and potential dangers of stopping proton pump inhibitors for gastric acid analysis; the recognition than many of the current assays used to assess gastrin concentrations are unreliable; the development of sensitive imaging modalities that detect neuroendocrine tumors including an increasing number of the primary gastrinomas; the increased use of percutaneous or endoscopic ultrasound-directed biopsies/cytology and the general lack of availability of acid secretory testing. In this article we will discuss the basis for these controversies, review the proposed changes in diagnostic approaches and make recommendations for supporting the diagnosis of Zollinger–Ellison syndrome in the modern era.

Keywords:

• atrophic gastritis
• chromogranin A
• gastric acidity testing
• gastrinoma
• hypergastrinemia
• MEN1
• neuroendocrine tumor diagnosis
• proton pump inhibitor
• secretin test
• Zollinger–Ellison syndrome

Financial & competing interests disclosure

This study was partially supported by intramural funds from the NIDDK, NIH (DK053200–26). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Notes

† ZES patients postincomplete gastrinoma resection [51], MEN1/ZES patients posteffective parathyroidectomy (usually 3.5–4 gland resection) for hyperparathyroidism [52] and uncommonly other ZES patients (0–2%) [42] can have a normal FSG.

‡ The role of imaging for diagnosis of ZES has not been systematically studied and is not clearly defined at present.

§ Achlorhydria is a well-recognized cause of false-positive secretin testing [79,116].

† Under such conditions a NET is confirmed but since MEN1 patients develop multiple NETs in various locations NET(s) identified on SRI may not be a gastrinoma(s) [8,8,18,18,33,33,162,162].

‡ Five biopsies (2-antrum, 2-corpus,1- incisura angularis) of the stomach are recommended to diagnose atrophic gastritis) [124,125].

§ SRI can be positive in nonngastrinoma NETs, numerous other tumors and both physiological and pharmacologic processes [see text], so alone is not specfic for gastrinoma [107,108,135].

† The potential for a false-positive secretin test in patients with hypo-/achlorhdria limits the usefulness of the secretin test in patients taking PPIs unless the gastric pH ≤ 2.

‡ Under these conditions a NET is likely but since MEN1 patients develop multiple NETs in various locations NET(s) a positive SRI or biopsy may not be a gastrinoma(s) [8,18,33,162].

§ Five biopsies (2-antrum, 2-corpus,1- incisura angularis) of the stomach are recommended to diagnose atrophic gastritis) [124,125].

¶ Biopsy and autoimmune markers can both be negative in confirmed autoimmune gastropathy [124,125].

# Prominent gaastric folds are present in 92% of ZES patients when initially seen, however they are not specific for ZES [2].